Systemic anaplastic large cell lymphoma (ALCL) is the most common and the second most common T-cell lymphoma in children and adults, respectively. ALCL have an abnormal chromosome translocation t(2;5)(p23;q35), which results in a fusion gene composed of nucleophosmin (NPM) and a truncated tyrosine kinase, named anaplastic lymphoma kinase (ALK). Abnormal expression of the NPM-ALK fusion protein leads to the auto-activation of ALK. The activation of ALK has been demonstrated to be lymphomagenic both in vitro and in vivo. However, the ALK-triggered cellular signaling pathway(s) is not fully understood. Biochemical studies have shown that cellular ALK binds to several signaling molecules of the p44/42 mitogen-activated protein kinase (p44/42 MAPK) cascade. In addition, our preliminary studies demonstrated that p44/42 MAPK is highly activated in ALCL lymphoma cells and down-regulating the cellular p44/42 MAPK signaling pathway inhibits ALCL cell growth/ proliferation and induces lymphoma cell apoptosis. These findings lead us to the hypothesis that the cellular p44/42 MAPK signaling pathway plays an essential role in mediating the ALK-induced lymphomagenesis of ALCL. [unreadable] [unreadable] To confirm our hypothesis, our studies will 1) Identify the role(s) of p44/42 MAPK signaling pathway during in vitro cell transformation/ lymphomagenesis of ALCL cells using a soft agar cell colony formation assay; 2) Determine the functional relationship between the p44/42 MAPK activation and abnormal NPM-ALK expression by establishing the ALCL cell models with inducible siRNA to specifically silence ALK gene in ALCL cells. [unreadable] [unreadable] Together, these studies will help us to understand the molecular mechanisms of ALCL development mediated by ALK and the p44/42 MAPK signaling pathway. More importantly, the resultant findings may lead to therapeutic advances for ALCL by identifying key signaling molecules in the lymphoma cells. [unreadable] [unreadable] [unreadable]